Apparatus, systems and methods for determining tissue oxygenation

ABSTRACT

A surgical instrument may be configured to sense a light re-emitting probe to resolve tissue oxygenation, the surgical instrument including: an optical emitter configured to excite the light re-emitting probe within an absorption band of the light re-emitting probe; an optical detector configured to receive the re-emitted light from the probe; and a signal processor configured to resolve the tissue oxygenation based on the received light. The surgical instrument can be a surgical stapler anvil or a flexible substrate having a tissue interfacing surface. Further, a monitoring device may be configured to map oxygenation of a tissue containing a light re-emitting probe, the monitoring device including: an optical emitter configured to excite the light re-emitting probe; at least one optical detector configured to receive the re-emitted light from the probe; and a signal processor that is configured to resolve the tissue oxygenation at multiple points to generate an oxygen map.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/220,034 filed Mar. 19, 2014, which claims priority to U.S.Provisional Patent Application No. 61/803,451, filed Mar. 19, 2013,which is hereby incorporated herein by reference in its entirety.

GOVERNMENT INTEREST

This invention was made with Government Support under NationalInstitutes of Health grant no. CA153571. The Government has certainrights in the invention.

TECHNICAL FIELD

The present invention relates to systems, methods and medical devicesfor use with molecular probes for resolving tissue oxygenation. Moreparticularly, the inventions are directed to systems, methods andmedical devices with sensors used to detect properties of biologicaltissue and a system for resolving the information gathered by thesensors.

BACKGROUND

A living organism is made up of cells. Cells are the smallest structurescapable of maintaining life and reproducing. Cells have differingstructures to perform different tasks. A tissue is an organization of agreat many similar cells with varying amounts and kinds of nonliving,intercellular substances between them. An organ is an organization ofseveral different kinds of tissues so arranged that together they canperform a special function.

Surgery is defined as a branch of medicine concerned with diseasesrequiring operative procedures.

Although many surgical procedures are successful, there is always achance of failure. Depending on the type of procedure these failures canresult in pain, need for re-operation, extreme sickness, or death. Atpresent there is no reliable method of predicting when a failure willoccur. Most often the failure occurs after the surgical procedure hasbeen completed. Failures of surgical procedures can take many forms. Themost difficult failures to predict and avoid are those that involvebiological tissue. This difficulty arises for three distinct reasons.Firstly, the properties that favor the continued function of biologicaltissue are very complex. Secondly, these properties are necessarilydisrupted by surgical manipulation. Finally, the properties ofbiological tissues vary between patients.

During a surgical operation, a variety of surgical instruments are usedto manipulate biological tissues. However, traditional surgicalinstruments do not have the ability to obtain information frombiological tissues. Obtaining information from the biological tissuesthat surgical instruments manipulate can provide a valuable dataset thatat present is not collected. For example, this dataset canquantitatively distinguish properties of tissues that will result insuccess or failure when adapted to specific patient characteristics.

What is needed are medical devices, systems and methods that can adaptto patient-specific characteristics that are of importance in avoidingsurgical procedure failure.

BRIEF SUMMARY OF THE INVENTION

A surgical instrument is configured to sense a light re-emitting probeto resolve tissue oxygenation. The surgical instrument includes at leastone optical emitter that is configured to excite the light re-emittingprobe within an absorption band of the light re-emitting probe; at leastone optical detector configured to receive the re-emitted light from theprobe; and a signal processor that is configured to resolve the tissueoxygenation based on the received light.

The surgical instrument further includes an applicator configured toprovide a target tissue with a medium, the medium containing the lightre-emitting probe. The signal processor is configured to resolve thetissue oxygenation based in a lifetime of the re-emitted light. Thesurgical instrument is a surgical stapler anvil. The applicator is atleast one injector that is configured to inject the medium into thetarget tissue. The surgical instrument further includes an interrogatorinstrument that is configured to interrogate the tissue. The surgicalinstrument is a flexible substrate having a tissue interfacing surface.The signal processor makes a determination of an operation success basedon the resolution of the tissue oxygenation. The surgical instrumentfurther includes a temperature sensor that is configured to detect atemperature of the tissue and at least one sensor configured to monitorinteraction forces of at least one of compression pressure and tissuetension of the tissue. The probe is a phosphorescent probe that hasmultiple absorption wavelengths. The surgical instrument iscommunicatively coupled to a base station.

A surgical stapler anvil is configured to sense a light re-emittingprobe to resolve tissue oxygenation. The surgical stapler anvil includesat least one optical emitter that is configured to excite the lightre-emitting probe; at least one optical detector that is configured toreceive the re-emitted light from the probe; and a signal processor thatis configured to resolve the tissue oxygenation based on the receivedlight.

The surgical stapler anvil is communicatively coupled to a base station.The signal processor makes a determination of an operation success basedon the resolution of the tissue oxygenation. The surgical stapler anvilfurther includes a temperature sensor that is configured to detect atemperature of the tissue. The surgical stapler anvil further includesat least one sensor configured to monitor interaction forces of at leastone of compression pressure and tissue tension of the tissue.

A monitoring device is configured to sense a light re-emitting probe toresolve tissue oxygenation. The monitoring device includes a flexiblesubstrate having a tissue interfacing surface, the tissue interfacingsurface containing (1) at least one optical emitter that is configuredto excite the light re-emitting probe; and (2) at least one opticaldetector configured to receive the re-emitted light from the probe; anda signal processor that is configured to resolve the tissue oxygenationbased on the received light.

The monitoring device includes at least one injector configured toinject a medium into target tissue, the medium containing the lightre-emitting probe. The monitoring device is communicatively coupled to abase station. The signal processor makes a determination of an operationsuccess based on the resolution of the tissue oxygenation. Themonitoring device further includes a temperature sensor that isconfigured to detect a temperature of the tissue. The the flexiblesubstrate is configured to be one or more of: (1) affixed to skin and(2) affixed to an internal tissue. The monitoring device is at leastpartially bioabsorbable.

A monitoring device is configured to map oxygenation of a tissuecontaining a light re-emitting probe. The monitoring device includes atleast one optical emitter that is configured to excite the lightre-emitting probe; at least one optical detector configured to receivethe re-emitted light from the probe; and a signal processor that isconfigured to resolve the tissue oxygenation at multiple points togenerate an oxygen map.

The monitoring device further includes at least one injector configuredto inject a medium into target tissue, the medium containing the lightre-emitting probe. The monitoring device further includes a temperaturesensor that is configured to detect a temperature of the tissue. Theoptical detector is at least one of a CCD array, a CMOS image sensor anda camera. The monitoring device is an endoscopic instrument. Themonitoring device is ingestible.

Additional features, advantages, and embodiments of the invention areset forth or apparent from consideration of the following detaileddescription, drawings and claims. Moreover, it is to be understood thatboth the foregoing summary of the invention and the following detaileddescription are exemplary and intended to provide further explanationwithout limiting the scope of the invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1a shows a representative embodiment of a surgical instrument withsensing capabilities.

FIG. 1b shows a generic embodiment of a medical device with features.

FIG. 2 shows a representative embodiment of a surgical instrument takingthe form of an interrogator with sensing capabilities.

FIG. 3 shows a representative embodiment of a minimally invasivesurgical instrument taking the form of an interrogator with sensingcapabilities.

FIG. 4a shows a representative embodiment of a surgical instrumenttaking the form of surgical stapler anvil with sensing capabilities.

FIGS. 4b and 4c show another representative embodiment of a surgicalinstrument taking the form of surgical stapler anvil with sensingcapabilities integrated into the staple form.

FIG. 4d shows a generic embodiment of a surgical instrument taking theform of surgical stapler anvil with sensing capabilities.

FIG. 5 shows a representative embodiment of an oxygen mapping systemtaking the form of a minimally invasive instrument with integratedapplicator.

FIGS. 6a and 6b show a representative embodiment of an implantablesensing device.

FIG. 7 shows a representative embodiment of a flexible mesh or patchwith integrated sensing capabilities at one or more points.

FIG. 8 shows a representative embodiment of an applicator integratedinto a surgical instrument, wherein the applicator is a micro needlearray.

FIG. 9a shows a representative embodiment of an applicator deliverysystem, wherein a medium is in a removable vessel.

FIG. 9b shows three states of the injector: the initial sealed state,the punctured state, and the expended state.

FIG. 10 shows a representative embodiment of an interrogator withcapabilities of manipulating an injected probe.

FIG. 11 shows an exemplary representation of a minimally invasive wandinterrogator surgical instrument.

FIG. 12 shows an exemplary embodiment of a medical device incorporatingsensing capabilities of the present invention.

FIG. 13a shows a representative embodiment of minimally invasive oxygenmapping system for ophthalmic surgery with an integrated applicator.

FIG. 13b shows a representative embodiment of an oxygen mapping systemas applied to retinal imaging.

DETAILED DESCRIPTION OF THE INVENTION

Each surgical procedure has the potential for failure. A commonprocedure in gastrointestinal surgery is a bowel resection—removing theaffected portion of the bowel and then mechanically joining the ends ofthe remaining segments to re-establish bowel continuity. The mechanicalconnection of the free ends of bowel forms what is termed a surgicalanastomosis. A surgical anastomosis is formed by either traditionaltechniques using suture material, or by contemporary techniques whichmay include utilizing surgical staplers or other surgical fasteningdevice. A surgical stapler mechanically joins the bowel by firing apattern of staples from a cartridge or housing through the two free endsof bowel against an anvil that ultimately forms a securing crimp on theopposing side. There are many embodiments of surgical staplers. Somestaplers form linear staple patterns, while others form circularpatterns. Some staplers incorporate functionality for cutting tissue.Many staplers have the ability to vary the gap between the base of thestaple and the formed crimp.

Anastomotic failure is one of the most feared complications ofgastrointestinal surgery due to the resultant morbidity and mortality.Failure of an anastomosis, or intestinal junction, can cause a spectrumof morbidities to the patient including local abscessformation—requiring procedural drainage, tumor recurrence, debilitatingpain, dysfunctional defecation, and overwhelming bacterial sepsisresulting in death. Despite improvements in surgical technique, thereremains limited ability to assess the anastomotic segment and predictoutcome, and as a result anastomotic failure occurs at unacceptably highlevels given the severe consequences. For example, in the performance ofa low anterior resection (LAR) for excision of rectal cancer,anastomotic failure has been reported to occur in up to 30% of cases.One large multicenter, observational study of 2729 patients reported aleak rate of 14.3%. These anastomotic failures cause a significant andavoidable economic burden on the healthcare system, as well as anincalculable amount of pain, suffering, and hardship for the patients inwhich the failure occurs. The devastating consequences of an anastomoticfailure are so severe that in the majority of cases surgeons performinga low anterior resection will opt to create a diverting ostomy at thetime of resection to mitigate the risks of anastomotic failure. In thesame study, 881 patients were given a temporary diverting ostomy while128 patients developed a leak. Up to 85 percent of those patientsunderwent an additional surgical procedure to reverse the ostomy thatprovided questionable benefit. While a diverting ostomy can avoid thedire consequences of anastomotic failure, it does not prevent failure,and poses a risk for additional complications. The morbidity rate for atemporary ostomy is 20-30%. Complications include intestinalobstruction, torsion, dehydration, electrolyte imbalance, stomalretraction, and severe skin breakdown. Additionally, complications ofostomy closure occur in a third of patients. Furthermore an ostomysignificantly compromises the lifestyle of the recovering patient.

There is neither a clinically practical apparatus that canquantitatively assess an anastomosis intra-operatively to determine thelikelihood of failure, nor an objective set of criteria by which asurgeon can select those patients that would benefit from divertingostomy. Nor is there a device that can help in determining the optimalplacement of an anastomosis.

There exists a need for a device, system and methodology for reducinganastomotic failures through the analysis of target tissues before,during, and after the creation of an anastomosis. There also exists aneed to objectively determine, at the time of surgery, those patientsthat would benefit from a diverting stoma procedure. There also exists aneed to deliver adjunct therapies to the anastomotic site to optimizeoutcome.

To accomplish its goal, one embodiment of the present inventioninterrogates the tissue, prior to creation of an anastomosis, to enablethe operative team to identify a suitable site based on quantitativecriteria. Another embodiment couples to the desired stapling platform,which includes traditional off-the-shelf disposable surgical staplers,and uses an array of multimodality sensors to measure the viability ofthe tissues during the creation of the anastomosis. If tissue parametersare unsuitable for an anastomosis, the operative team can takecorrective action, thus reducing the risk of anastomotic failure. At theconclusion of the formation of the anastomosis, the operative team canensure tissue measures remain within acceptable range. If the measuresare abnormal, the operative team can again take corrective action toimprove outcome. Measurements may be made from the internal and/orexternal surface of the tissue.

One representative application of the present invention is in thetreatment of colorectal cancer. Colorectal cancer (CRC) is the thirdmost common cause of cancer for men and women in developed countries.Estimates predict that worldwide just under 1.2 million new cases ofcolorectal cancer were diagnosed in 2007. Rectal cancer accounts forapproximately 27% of all colorectal cancers and presents the formidablechallenge of ensuring a curative resection while maintaining acceptablefunction. The mainstay of treatment for rectal cancer is surgicalresection—removing the affected portion of the bowel and performing ananastomosis on the ends of the remaining segments to re-establish bowelcontinuity. The end-to-end anastomosis (EEA) is most commonly performedusing circular EEA staplers. As with any surgical procedure, resectionof a rectal cancer can have complications. Amongst all of the possiblecomplications the three most devastating to the patient in terms ofmorbidity and mortality are tumor recurrence, anastomotic leak andanastomotic stricture. Tumor recurrence can be reduced by: followingoncologic principles of dissection, providing appropriate adjunctivechemotherapeutic, photodynamic, and radiation therapies, and preventingextra-luminal extravasation of residual intra-luminal neoplastic cellsthrough anastomotic breakdown. Anastomotic failure has been anecdotallyattributed to inadequate tissue perfusion and excessive tension at theanastomosis.

When determining the location of a rectal cancer the surgeon notes thedistance of the tumor from the anal verge. The anal canal extends from0-4 cm past the anal verge, and the rectum 4-19 cm. Surgically therectum extends from the anal sphincters to the sacral promontory. Thelocation of the cancer dictates the type of surgical procedureperformed.

The primary goal of a curative resection is to remove all potentialtissues harboring cancerous cells. To accomplish this goal, the surgicalteam aims to resect the tumor with a cancer free margin as well as thetumor's blood supply and draining lymphatic tissue. Tumors located inthe upper rectum, greater than 12 cm from the anal verge, are regularlyamenable to an anterior resection (AR). Those in the mid rectum, between6-12 cm, are subject to a LAR with or without a total mesorectalexcision (TME), and tumors in the lower rectum, 4-6 cm, are usuallytreated with an ultra-low anterior resection (ULAR), incorporating aTME, and either a colorectal or coloanal anastomosis. A total mesorectalexcision is a technique that attempts to resect the rectum and allinvesting soft tissues en-bloc. This technique has been touted in theliterature as having superior results in terms of minimizing local tumorrecurrence, however it is speculated that the procedure has an inverseeffect on leak rates due to the excision of the supplying vasculature tothe anastomotic site. Every attempt is made to retain fecal continence,however those tumors involving the anal sphincters 0-4 cm are resectedthrough a sphincter sacrificing abdominoperineal resection (APR). Thepresent invention may be used to determine surgical resection marginsand anastomosis location based upon sensor measurements. Thesemeasurements may be performed on the internal and/or external surface ofthe tissue and be interrogated as a single point or multiple locations.

As a secondary goal the surgical team strives to restore continuity ofthe bowel and ensuing fecal stream. To accomplish this goal ananastomosis is formed. Simply, an anastomosis is the surgical connectionof two free ends of a tubular structure. When the continuity of thebowel cannot be restored, the fecal stream is diverted through a stoma,or opening, in the anterior abdominal wall through which the patienteliminates into an ostomy bag. There are two main reasons for stomaformation: resection of the anal sphincter complex, and diversion of thefecal stream. In a sphincter sacrificing procedure such as an APR, thepatient is dependent on a permanent ostomy. With a sphincter sparingprocedure such as a LAR, the fecal stream may diverted through atemporary ostomy in order to mitigate the risk of overwhelming sepsisresulting from fecal contents entering the abdominal cavity should therebe a leak at the anastomosis. Most of the time a temporary stoma can bereversed within a few months after the initial operation through aseparate procedure. The present invention may be used to assess theviability of the anastomosis and/or stoma based upon sensormeasurements.

The scientific literature suggests that the cause of anastomotic failureis that inadequate tissue perfusion as a result of redefinedvasculature, tissue interaction forces, edema, and tension result in adecrease of oxygen delivered to the anastomotic site. Without adequateoxygen delivery, efficient aerobic cell respiration cannot occur withinthe native cells leading to tissue degradation; collagen matrix cannotmature into strong collagen fibrils; and white blood cells cannoteffectively fight bacterial invasion.

Normal healing of a gastrointestinal anastomosis follows an orderlyreparative process. The inflammatory phase occurs immediately afterdisruption of the tissue and lasts 2-3 days. This phase is characterizedby efflux of inflammatory cells into the wound. Increased permeabilityof vessels adjacent to the wound facilitates the delivery of targetcells. Hemostasis is achieved through a platelet mediated fibrin basedclot. Neutrophils initially dominate this phase with the goal of killinginvading microbes. Macrophages appear next and secrete tissue growthfactors that are paramount to progressive repair. The proliferativephase begins with the arrival of fibroblasts. The fibroblasts replacethe provisional clot matrix with a loosely organized collagen framework.In this phase the anastomosis first weakens as collagen lysis initiallyoutpaces synthesis. Colonic anastomoses lose up to 70% of their initialstrength. Collagen synthesis requires hydroxylation of lysine andproline residues. Cofactors essential for this process are oxygen,ferrous iron, Vitamin C, and alpha-ketoglutarate. Angiogenesis beginsduring this stage to increase oxygen and nutrient delivery to meet theincreased metabolic demands of the healing wound. The final remodelingphase is characterized by the conversion of the relatively weak collagenfrom the previous phase into thick high strength collagen bundles.

The adequate supply of oxygen is of paramount importance in each phaseof wound healing. During the inflammatory phase oxygen providesneutrophils with the critical ability to kill bacteria throughsuperoxide generation. In the proliferative and remodeling phases oxygenis a key factor in collagen formation. Likewise oxygen provides fornormal aerobic metabolism of the injured tissue.

The gastrointestinal tract, with the exception of the esophagus andlower rectum, is comprised of four layers: the outer serosa, themuscularis propria, the submucosa, and the mucosa. The submucosaconsists of a layer of fibroelastic collagen matrix containing bloodvessels and nerves. Halsted was the first to determine that the strengthof the intestine is derived from the submucosal layer. It is thecollagen fibrils within the submucosa that are mainly responsible foranastomotic integrity. Low collagen content is associated with reducedanastomotic bursting strength.

The etiology of anastomotic failures has been attributed to a variety oflocal and systemic factors. Local factors include tissue hypoperfusion,anastomotic tension, poor apposition of wound edges, radiation injury,and distal obstruction. The first three local factors contributing tofailure are affected by surgical manipulation of tissues. Oxygendelivery to tissues is a function of the oxygen content of bloodmultiplied by the blood flow rate within a volume of tissue. Bloodoxygen content (BOC) of whole blood is given by the followingexpression:

BOC=Oxygen bound to hemoglobin+Dissolved Oxygen

BOC=1.34*Hb*SO2+0.003*PO2

Where, 1.34 (ml/g) is the amount of oxygen functionally carried by onegram of circulating hemoglobin, Hb (g/dl) is hemoglobin, SO2 is percenthemoglobin oxygen saturation, 0.003 (ml/100 ml/mmHg) is the solubilityof O2 in plasma at 37° C., and PO2 (mmHg) is the partial pressure ofoxygen within the blood. Under normal physiologic conditions (Hb=15g/dl, SO2=0.98, and PaO2=100 mmHg), BOC is 20 ml O2/100 ml arterialblood.

As arterial blood flows through the capillary beds of the intestine, theblood cell hemoglobin desaturates as oxygen diffuses toward thesupported tissue. The degree of desaturation from tissue oxygenextraction varies based on the flow of oxygenated blood through thetissue as well as the metabolic needs of the target tissue.Auto-regulation in the intestinal microcirculation allows for flowadjustment within limits responsive to demand. Under the normal flowconditions in canine ileum of 30-140 ml/min/100 g of tissue, oxygenextraction is flow-independent. The tissue is able to extract anadequate amount of oxygen to support aerobic cellular metabolism. Flowrates less than 30 ml/min/100 g oxygen extraction is flow-dependent andthe tissues may not be able to support aerobic metabolism. Human smallintestine has the same threshold for flow dependent oxygen. Hypovolemiaand shock are contributing factors to anastomotic failure, wherenormovolemic anemia is tolerated if perfusion is adequate.

Surgical manipulations of anatomy during bowel resection as well as thecreation of a surgical anastomosis cause a perturbation in tissueperfusion. A canine model demonstrated a reduction in mucosal blood flowat an end to end colonic anastomosis regardless of the techniqueemployed. However, the absolute reduction is dependent on technique.Using a circular stapler, an anastomosis formed with a staple gap equalto the measured thickness of the interposed bowel walls yielded a 43percent reduction in blood flow, whereas a staple gap of half themeasured thickness yielded a 71 percent flow reduction. A single layersutured anastomosis resulted in a 27 percent flow reduction while a 59percent flow reduction was recorded in a two layered suturedanastomosis. Perianastomotic serosal measurements were takenintra-operatively on both the proximal and distal aspects of theanastomosis within 1 cm of the suture line. Altered perfusion at therectal stump correlated with subsequent anastomotic leaks. Blood flowwas measured by laser Doppler at the proximal side of an end-to-endcolorectal anastomosis reveals a significant reduction in flow afterrequisite dissection. In summary, anastomotic failure occurs whenperfusion fails to provide the inputs needed to support tissue healing.

One representative application of the present invention is in theperformance of a bowel resection secondary to a bowel obstruction. Oftena mechanical bowel obstruction is caused by an adhesion which causes thebowel to twist upon itself, or a hernia which incarcerates orstrangulates the bowel. The blood supply to the bowel can be compromisedleading to ischemia, or infarction. Intra-operatively, the surgeonqualitatively determines if the bowel is viable after it has beenuntwisted or freed. If the bowel does not appear viable the bowel isresected. Often qualitative methods are not accurate in determiningbowel viability. If the bowel ‘pinks up’ then it may be salvageable.Questionable segments of bowel are either resected during the initialsurgical procedure or left to ‘declare themselves’ over a number ofhours resulting in the performance of a ‘second look’ operation todetermine bowel viability. An advantage of the present invention is theability to quantitatively assess bowel oxygenation at the time ofsurgery to ensure viability. If a segment is not viable and needs to beresected, the present invention can guide the surgeon in selection of aviable resection margin. The anastomosis is then performed on tissue inwhich normal perfusion has been confirmed.

One representative application of the present invention is in thecreation and monitoring of tissue flaps. Cancer of various types, i.e.breast, skin, etc., often cause removal of significant volumes of tissueduring an attempt at curative resection. Traumatic injury may result insevered limbs or avulsed portions of tissue. The resulting tissue lossis often replaced by native tissue transposed from other parts of thepatient's body. Free tissue flaps are flaps that are completely removedfrom their native position along with the supplying vascular pedicle.The free flap vasculature is then reconnected to vessels near the tissuevoid. The vascular anastomosis may fail due to leakage, stricture, orocclusion from inappropriate clot formation. The present inventionenables resolution of flap oxygenation in either a point or areafashion, both for the intra-operative confirmation of tissue perfusion,and post-operative monitoring. Current technology is limited toqualitative measures of blood flow. The present invention presents realtime quantitative assessment of tissue oxygenation.

One representative application of the present invention is in themonitoring of patient oxygenation. A current method of continuously andnon-invasively monitoring a patient's oxygenation is through the use ofpulse oximetry. In pulse oximetry the patient's blood is interrogatedwith light to determine the percentage of blood that is saturated withoxygen. Unfortunately this technique is limited by technical andphysiologic factors. Ambient light and motion affect the pulseoximeter's ability to render a suitable signal. Poor blood flow incritically ill patients can often render pulse oximetry useless as thepulsatile signal cannot be resolved. The present invention enables anaccurate measure of tissue oxygenation independent of blood flow in arobust manner.

One representative application of the present invention is in themonitoring of a disease state of the brain. There are numerousconditions (trauma, stroke, procedures, cancer, infection, inflammation,etc) that can affect brain perfusion/oxygenation, whether throughprimary means such as vessel occlusion or hemorrhage; or throughsecondary means by alteration of intracranial pressure. Currenttechnology fails to provide real time measurement of direct brainoxygenation/perfusion. The present invention provides for real timemeasurement of brain perfusion/oxygenation through trans-cranial,intra-cranial, or extra-cranial means. The device can be positioned onan infant, over the fontanel in order to interrogate underlying braintissue. Alternatively the device can be placed intra-cranially through atrans-cranial port, or implanted in the brain tissue to allow forcontinuous monitoring over extended periods of time. The device can bepositioned on the eye to interrogate the internal structures such as theoptic nerve, or retina.

One representative application of the present invention is in themonitoring of organs. In this application the device can be temporarilyplaced or permanently implanted into or on the surface of an organ.Alternatively the device can be ingestible to monitor thegastrointestinal tract. An ingestible device could map the oxygenation,and/or other physiological parameters of the GI tract.

The present invention includes a surgical instrument, probes, andmethods for assessment of phosphorescent or fluorescent lifetime of aninjectable probe or natural auto fluorescence. In one configuration, atleast one sensor is configured to obtain biological tissue oxygenationutilizing the technique of oxygen dependent quenching of phosphorescenceof an injectable probe. In another embodiment, the present inventionmeasures lifetime of a marker or other probe in or on the body. In afurther embodiment, lifetime of phosphorescence or fluorescence producedfrom native biologic tissue is assessed.

Other potential applications include but are not limited to themonitoring/recording of a transplanted organ or appendage,intra-cranial, intra-thecal, intra-ocular, intra-otic, intra-nasal,intra-sinusoidal, intra-pharyngeal, intra-laryngeal, intra-esophageal,intra-tracheal, intra-thoracic, intra-bronchial, intra-pericardial,intra-cardiac, intra-vascular, intra-abdominal, intra-gastric,intra-cholecystic, intra-enteric, intra-colonic, intra-rectal,intra-cystic, intra-ureteral, intra-uterine, intra-vaginal,intra-scrotal; intra-cerebral, intra-pulmonic, intra-hepatic,intra-pancreatic, intra-renal, intra-adrenal, intra-lienal,intra-ovarian, intra-testicular, intra-penal, intra-muscular,intra-osseous, and intra-dermal physiologic/biomechanical parameters.

The present invention relates to medical devices capable of measuringphysiologic and mechanical properties of tissue. One embodiment of theinvention relates to coupling sensing elements with a surgicalinstrument to determine tissue viability during surgery by measuring theoptical time response from a light re-emitting medium. In a specificembodiment, an oxygen-sensitive phosphorescent oxygen sensing probe isinjected into tissue, and a laparoscopic interrogator uses opticalsensing elements to determine tissue oxygenation based on the opticalresponse (i.e. lifetime) of light emitted by the phosphorescent probe.

The sensing elements associated with the invention may sense mechanicalor biological properties. The sensing instruments may include one ormore sensing modalities. The sensing modalities may include mechanical,optical, chemical, electrical, or other means for generating a signalindicative of a property of a subject tissue. In one embodiment, thesensing elements measure oxygenation through the use of a mediumcontaining a phosphorescent probe or phosphor delivered into tissue.Other embodiments measure oxygenation through oximetry-based techniques.Further embodiments measure perfusion or flow rates through the timeresponse of a fluorescent or phosphorescent medium introduced into thetissue.

In an embodiment, the sensing elements are incorporated into, or coupledto, the working surface (i.e. tissue contacting surface) of a surgicalinstrument for manipulating biological tissue. Instruments may includetraditional open, laparoscopic, endoscopic, bronchoscopic, otoscopic,opthalmoscopic, laryngoscopic, cystoscopic, colposcopic, intravascular,intraluminal, robotic, or other minimally invasive tools such as apurpose-built tissue interrogator or instrumented standard instrumentsuch as a grasper, needle driver, stapler, clip applier, catheter,scissor, cautery, or retractor. Instruments may also includeinterrogators or other devices that may or may not be minimally invasiveand may interrogate the internal and/or the external surface of tissue.

The sensing elements may include mechanical and optical sensingmodalities. Mechanical sensing includes, but is not limited to, pressuresensors that monitor tissue interaction forces including compressionpressure and tissue tension. Optical sensing elements include but arenot limited to light emitters including light emitting diodes (LEDs),broad band light sources, and laser diodes (LDs), and light receiversincluding photodiodes (PDs) and silicon photomultipliers (SiPMs), CCDarrays, CMOS imaging sensors, cameras, and spectrometers. The sensorsmay make measurements at a single discrete location or at a plethora oflocations. The optical sensing elements are configured to measure atleast one of tissue oxygenation, oxygen delivery, oxygen utilization,tissue characterization, and tissue general health using oximetry,phosphorescent techniques, or spectroscopic techniques, and at least oneof tissue perfusion, tissue flow dynamics, tissue oxygen content, tissuechemical composition, tissue immunologic activity, tissue pathogenconcentration, or tissue water content using fluorescence orphosphorescence based techniques. The fluorescence and phosphorescencebased techniques include but are not limited to the following:monitoring and analyzing the intensity and time course of a fluorescentor phosphorescent response responsive to the injection or activation ofa fluorescent or phosphorescent medium (e.g., fluorescein or indocyaninegreen injection), determining oxygen quantities by measuringoxygen-dependent quenching of fluorescent or phosphorescent radiationusing a sensitive material (e.g., ruthenium) by both intensity andtime-resolved methods, determining oxygen concentration based on thequenching time response (lifetime) of injectable oxygen sensitivephosphorescent probes (e.g., oxygen-dependent quenching phosphorescentnano sensors), and determining the target tissue property byquantitative fluorescent or phosphorescent methods (including the use ofquantum dots, or other biomarkers incorporating light re-emittingproperties). In one configuration the device senses perfusion usingflourescein, or IC green, or other imaging agent. In one otherconfiguration the device senses native oxygen quenching orphosphorescence.

Measurement of tissue oxygenation or other tissue characteristics can bemeasured in a gated fashion to standardize the measurement and allow forcomparison. One representative example of said gated measurement is themeasurement of tissue oxygenation at a known interaction force(s) suchas compression pressure. Measurements may also be gated to physiologicparameters such as respiration and cardiac output.

PCT Patent Application No. PCT/US2006/013985, which is herebyincorporated herein by reference in its entirety, describes a system andmethodology for using the information gathered by surgical instrumentshaving sensors in an adaptive, patient-specific manner. The presentinvention can be used to predict outcome, the likelihood of success orof failure, or guide surgical procedure, and as described inPCT/US2006/013985, US Patent Application Publication No. 2012/0116185,which is hereby incorporated herein by reference in its entirety, andU.S. Pat. No. 8,118,206, which is hereby incorporated herein byreference in its entirety. Furthermore the present invention can beconfigured as an adjunct sensing system, and as described in US PatentApplication Publication No. 2012/0116185 and U.S. Pat. No. 8,118,206.Additionally, the present invention can be powered by radiofrequencytechniques, and as described in US Patent Application Publication No.2010/0081895, which is hereby incorporated herein by reference in itsentirety.

Tissue parameters can be measured by a variety of methods. One techniqueutilized by the present invention measures tissue oxygenation levels viautilizing oxygen dependent quenching of phosphorescence via a systemicor locally injected phosphorescent oxygen sensing molecular probe foroxygen measurements. See, for example, U.S. Pat. No. 4,947,850, which ishereby incorporated herein by reference in its entirety, U.S. Pat. No.5,837,865, which is hereby incorporated herein by reference in itsentirety, U.S. Pat. No. 6,362,175, which is hereby incorporated hereinby reference in its entirety, U.S. Pat. No. 6,165,741, which is herebyincorporated herein by reference in its entirety, U.S. Pat. No.6,274,086, which is hereby incorporated herein by reference in itsentirety, U.S. Pat. No. 7,575,890, which is hereby incorporated hereinby reference in its entirety, and US Patent Application Publication No.2013/0224874, which is hereby incorporated herein by reference in itsentirety. The phosphorescent oxygen sensing probe can include aphosphorescent metalloporphyrin core encapsulated inside hydrophobicdendrimers, which form a protecting shell that isolates the chromophorefrom direct contact with the environment, controls oxygen diffusion, andenables control over the probe's dynamic range and sensitivity. Themetalloporphyrin core can be constructed with different elements.Palladium (Pd) and platinum (Pt) are two elements that can be utilized.The advantage of a platinum based core over a palladium based core isits quantum efficiency. The increase in the quantum efficiency of thephosphor allows for a significant increase of light output when comparedto the Pd based molecule; more light returned per molecule allows forthe use of fewer molecules to achieve the same signal returned to thedevice. Alternatively injection of the same amount of molecule enablesthe use of less sensitive (less expensive) photo-detectors. PeripheralPEGylation of the dendritic branches ensures high aqueous solubility ofthe probe whilst preventing interactions with biological macromolecules.The overall size of the molecular probe affects the probe's ability tobe cleared by the kidney. Faster clearance limits the agent's exposureto the patient. The size can be varied through the modification of thedendrimer length, number of dendrimers, and the extent of PEGylation.

In one embodiment of the probe, the core,Pd-meso-tetra-(3,5-dicarboxvphenyl)tetrabenzoporphyrin (PdTBP), isencapsulated by eight generation 2 poly-arylglycine (AG2) dendrons; eachof which are PEGylated with monomethoxy-polyethyleneglycol amine(PEG-NH2) groups (Av. MW 1,000 Da), having on average 21-22 monomeric—(CH2CH2O)— units. The molecular weight of the probe dendrimer was foundto be in the range of −26,000-44,000 Da with a maxima of 35,354 Da asdetermined by MALDI mass spectroscopy. The phosphorescence quenchingmethod relies on the ability of molecular oxygen (O2) to quenchphosphorescence of excited triplet state molecules in the environment.In biological systems phosphorescence quenching by oxygen occurs in adiffusion controlled fashion and is highly specific to O2, since O2 isthe only small-molecule dynamic quencher present in sufficiently highconcentrations. The dependence of the phosphorescence lifetime (t) onthe partial pressure of oxygen (pO2) through the range of biologicalconcentrations is well described by the Stern-Volmer equation:1/τ=1/τ0+kq×pO2, where T is the phosphorescence lifetime at a specifiedoxygen pressure pO2, τ0 is the phosphorescence lifetime in the absenceof oxygen (pO2=0), and kq is the quenching constant. One molecularoxygen probe has a quenching constant, kq, of approximately 326mmHg⁻¹s⁻¹, and a τ0 of 210 μs over the range of physiologic pH, 6.2-7.8,and constant temperature of 36.5° C. The calibration parameters of saidprobe, kq and τ0, change linearly with respect to temperature. Thequenching constant, kq, increases from 211 mm Hg⁻¹s⁻¹ to 338 mmHg⁻¹s⁻¹with the rise of temperature from 22° C. to 38° C., which corresponds tothe temperature coefficient of 7.8 mm Hg⁻¹s⁻¹/° C. The absorptionspectrum of said probe has maxima at approximately 448 nm and 637 nmwith a phosphorescence emission maximum of 813 nm. Excitation atmultiple wavelengths (either separately or simultaneously) confers anapplication specific advantage of being able to interrogate anddistinguish tissue properties at differing penetration depths or layers.A combination of multiple pO2 values in a field of view (e.g., wheredifferent tissue layers are differently oxygenated) will manifest itselfas a combination of lifetimes (a sum of exponential decays); multiplepO2 values and corresponding concentrations can be determined throughmeans described herein.

FIG. 1a shows a representative system with sensing capabilitiesaccording to an embodiment of the present invention. This embodimentspecifically depicts a surgical instrument 101, wherein the instrumentis a minimally invasive device for manipulating biological tissue. Theinstrument may be designed for open, laparoscopic, endoscopic, or othersurgical approaches as previously noted. The instrument interacts withtissue of body 103. In one embodiment, said tissue is intestinal tissue107. One configuration of instrument 101 incorporates jaws 109 and 111to interact with tissue 107. In one embodiment, one or more jaws 109 and111 contain sensors or sensing elements 110 and 112 for measuringbiological or mechanical properties of tissue 107. In a furtherembodiment, the jaws are configured to ensure constant compressionpressure of tissue 107 against sensing elements in jaws 109 and/or 111.One or more jaws may contain an inflatable cavity, bladder, balloon,catheter, compression plate, or pressure sensor 113 for compressingtissue against one or more sensing elements. Jaws 109 and 111 mayincorporate control electronics and sensing elements. Jaws 109 and 111are coupled to instrument 101 and may either be a fixed distance apart,be able to move in a parallel motion, or move in a hinged motion. In oneembodiment, the distal tissue contacting end of the instrument 101 isarticulated at a joint 114 with one or more degrees of freedom.

In one embodiment, jaws 109 and/or 111 contain an applicator capable ofdelivering a medium into tissue 107. The medium may incorporate afluorescent or phosphorescent oxygen sensing molecular probe. In oneembodiment, the applicator comprises one or more microneedlesincorporated into one of jaws 109 and 111. Said microneedles may takethe form of a molded needle array. In another embodiment, one of more ofjaws 109 and 111 incorporates needles with a porous surface fordelivering the medium into tissue 107. In another embodiment the needleshave at least one side hole, and an occluded tip. One embodiment of thepresent invention incorporates an integrated injection system. Theinjection system includes a vessel 117 that contains the medium 118. Themedium 118 that has been introduced into tissue 107 is identified as119. In one embodiment, the vessel 117 contains a number of metereddoses of a medium 118 comprising the phosphorescent oxygen sensingmolecular probe. Vessel 117 is coupled with the one or more needlesassociated with jaws 109 and/or 111.

In one embodiment, instrument 101 contains a handle or other component121 that encloses one or more of control electronics, battery powersources, user interfaces, displays, and a wired or wirelesscommunications interface. The instrument 101 or component 121 mayinclude controls for adjusting compression pressure between jaws 109 and111, articulating joint 113, administering injections from vessel 117,and operating sensing elements located in jaws 109 and/or 111. Component121 may be optionally detachable from instrument 101, allowing for apartially disposable configuration of 101, in which 121 is reusable. Thecontrol electronics in 121 or other location on instrument 101 maycommunicate with an external interface 125 through a wireless or wiredconnection 123. The external interface may take the form of a freestanding base station, a computer, a tablet style computing device orother portable electronic device with a display, or other device.External interface 125 may additionally be connected to an externalnetwork. Device 125 displays information to the clinician on display127. This information may include tissue oxygenation, blood flow, mapsof tissue oxygenation, compression pressure, warning information,predictions about the likelihood of success of the procedure, or otherphysiologic, mechanical, patient status, or situational information.Sensory substitution including audio, visual, vibration, or othertechniques may be provided by instrument 101 or external device 125.

FIG. 1b shows further detail of a representative medical device withsensing capabilities according to an embodiment of the presentinvention. A biological tissue 151 contains a medium 153. In oneembodiment of the invention, medium 153 contains a phosphorescent oxygensensing molecular probe injected into tissue 151. The medium may beintroduced systemically or may be injected locally. In one embodiment,one or more needles or delivery cannulas 157 with at least one orifice159 are used to locally inject medium 153. A medical device 155 isconfigured to interrogate tissue 151. Device 155 may also comprise anapplicator for delivery of a medium. In one configuration, needle 157 isa microneedle and orifice 159 is one or more holes on the lateral sideof said needle. A vessel or syringe 163 contains medium 165; medium 165is the same material as medium 153 prior to injection into tissue 151.An injector 167 may be used to inject medium 165 into tissue 151 asrepresented by medium 153 in the tissue. Injector 167 may be manuallycontrolled or may be motorized or otherwise actuated. Injector 167 maybe configured to provide metered doses of medium 165. Vessel 163 andinjector 167 may be an integral part of medical device 155, may be anaccessory to medical device 155, or may be configured as an independentinjection system. Medical device 155 contains at least one sensor 171,which further contains sensing elements 173 and 185. In one embodiment,sensing element 173 is a light emitter source that emits light 175 thatoptionally passes through an optical filter 177 into the medium 153 oftissue 151. Upon incident light 175, medium 153 re-emits an opticalresponse light 181. Optical response 181 optionally passes through anoptical filter 183 to an optical detector 185. A further sensor 187 mayprovide a measurement of contact or of pressure between a surface ofinstrument 155 and tissue 151. Components of sensor 171 are coupled withprocessor 189 that controls light source 173 and acquires signals fromdetector 185. Processor 189 controls light emission from 173 andprocesses signals from 185 so as to perform a sensing operation. In oneembodiment, a communication interface 191 communicates with an externalbase station or other device 195 through a link 197. Link 197 may be awireless communication between device 155 and base station or display195.

In one embodiment of the present invention, medium 153 and 165 containsfluorescent or phosphorescent oxygen sensing molecular probe. Lightsource 173 may be a narrow band light source such as an LED or laser, ormay be a broadband source such as a white light source. The peakemission wavelength of the narrowband source is selected to be at ornear an absorption peak of the probe (e.g., an excitation wavelength ofthe probe) in medium 153. Filter 177 may be used to further restrictincident light 175 to wavelengths in or near the absorption wavelengthregion of the probe. The probe re-emits light 181 which then optionallypasses through filter 183 to isolate the emission light 181 from theincident light 175. Light detector 185 senses the intensity of receivedlight 181. In one configuration, detector 185 is a single point detectorsuch as a PD, APD, SiPM, or similar device. In an alternateconfiguration, detector 185 is a multi-point detector such as a cameraor an array of single point detectors. The camera may be CCD, CMOS, orother technology and may be directly at the tissue contacting surface ofinstrument 155 or optically coupled at a remote location. The array ofsingle point detectors may be PD array, SiPM array, linear CCD or othertechnology. In one configuration, processor 189 commands light pulsesfrom source 173 and analyzes the time response of the signal received bydetector 185 using time domain signal processing techniques. In analternate configuration, processor 189 commands modulated light such asa sinusoidal intensity profile from source 173 and analyzes the measuredsignal from detector 185 to determine the phase lag through frequencydomain signal processing techniques. In one configuration the probe inmedium 153 quenches the lifetime of the phosphorescent re-emission inresponse to oxygen in the vicinity of the probe. This relationshipbetween oxygenation and phosphorescent lifetime may follow theStern-Volmer relationship. Time domain or frequency domain techniquesmay be used by the signal processor 189 to quantitatively resolve thecorresponding oxygen content or concentration in a location of tissue151. By resolve it is meant to calculate, compute, determine, assess, oracquire the solution for oxygen content or concentration in the targettissue. An exemplary implementation of said time domain or frequencydomain techniques is taught in U.S. Pat. No. 6,707,168-B1. Oxygencontent may be represented as a number or shown as a map of oxygenationon either device 155 or an external display unit 195. The oxygen contentmay be used to predict the likelihood of success or failure of thesurgical procedure, or guide a surgical procedure. An exemplaryimplementation of predictive or guidance techniques is taught in US2009/0054908 A1, which is hereby incorporated herein by reference in itsentirety. In one embodiment, instrument 155 is a minimally invasivesurgical instrument. In another embodiment, device 155 is an anvil of asurgical stapler. In another embodiment, device 155 is an adjunct to asurgical instrument, such as an accessory to a surgical stapler anvil.In another embodiment, device 155 is an internally implantable sensor.And in another embodiment, medical device 155 is an externally wearabledevice such as a patch or is an implantable sensor.

In one configuration of the present invention, the medical device (suchas a surgical instrument) 101 or 155 or other embodiments are configuredto sense oxygenation in multi-layered tissue, or to discriminateoxygenation at different depths of tissue. Using a phosphorescent oxygensensing probe having multiple absorption wavelengths in medium 119 or153, the instrument 101 or 155 can irradiate and excite a subset of theprobe injected into tissue 107 or 151 based on the excitation wavelengthemitted from device 101 or 155 since the penetration depth in tissue iswavelength-dependent. Oxygenation can be discriminated at two or moredepths or layers by exciting the tissue sequentially with multipleexcitation wavelengths at or near absorption peaks of the probe, anddetermining the corresponding quenching response. Sensing the deepervalues will be a summation of multiple layers, oxygenation at deeperlayers can be determined by accounting for the sensed oxygen atshallower layers. In an alternative approach, the phosphorescent decayof various oxygenation levels in heterogeneous luminescence systems(i.e. mixed oxygenations within the tissue sample) can be determinedthrough deconvolution methods to produce a spectrum of oxygenation.

In one embodiment of a sensing medical device, a plethora ofsinusoidally modulated excitation light outputs are generated (eithersimultaneously, separately, or combined into a time varying frequencysignal such as a chirp) and frequency domain techniques are utilized todetermine the spectrum of phase lag of the received signal from aninjected phosphorescent medium. By determining the relativecontributions of each phase lag, a quantitative spectrum of tissueoxygenation may be generated. In another embodiment, time domaintechniques are utilized to determine the time response of the medium toa pulse of light. Multiple exponential fitting of the decay can be usedto generate a quantitative spectrum of tissue oxygenation.

FIG. 2 shows a tissue interrogator. The interrogator 201 evaluatesproperties of tissue 203. In one embodiment, jaws 205 grasp tissue 203.A compression control device such as screw 207 or a compression device(e.g., a balloon or compression plate) affixed to jaws 205 regulatepressure on tissue 203. Sensing elements 211 are integrated into the oneor more tissue contacting surfaces. In one embodiment, an injectionsystem is incorporated into a cavity 213 of the device. Needles incavity 213 are used to deliver a medium 205 into tissue 203. In oneembodiment, a phosphorescent oxygen sensing probe 205 is injected intotissue 203. Sensing elements 211 obtain data to measure tissueoxygenation by illuminating tissue with a light source and assessing thetime response of the re-emitted light (i.e. phosphorescent quenchingtime response). Control electronics 215 operate the sensing elements 211and are communicatively coupled through 221 to communication interface223. Interface 223 is coupled through 225 to an external controller oruser interface 227.

FIG. 3 shows one embodiment of a wand-type tissue interrogator designedfor minimally invasive surgical interventions. Wand 301 contains lowerjaw 303 and upper jaw 305 to interact with (i.e. enclose) a biologicaltissue. Lower jaw 303 contains a compression device 309 to standardizeand maintain consistent compression pressure of the tissue. Upper jaw305 contains control electronics 311 and sensing elements on the tissuecontacting surface. In one embodiment, jaws 303 and/or 305 contain aninjection system for introducing a medium into the tissue. This mediummay include a phosphorescent oxygen sensing probe or another agentcapable of imaging, diagnostic, or therapeutic purposes. The applicatorinjection system 317 may be incorporated into the handle or body ofinstrument 301. This may include a vessel containing one or more dosesof the medium. A user can administer the dose precisely from theinstrument 301 to needles in jaws 303 and/or 305. The needle may bemicroneedles that may further take the form of a micromolded needlearray. They may also take the form of porous needles that saturate thetissue in the region for microinjection of the medium into the tissue incontact with the instrument jaws. Jaws 305 and 303 may be fixed relativeto each other, or able to open and close. The distal end of theinstrument may be articulated at joint 319. In one embodiment,instrument 301 fits through a standard laparoscopic surgical instrumentport and articulates at joint 319 to position jaws 303 and 305 around atissue. In one configuration, a tube 321 is used to inflate or otherwisecontrol compression device 309. In a further configuration, compressiondevice 309 is a balloon catheter. In another embodiment, a tube 321 isused to deliver the medium for injection into the tissue. In a furtherembodiment, the sensing instrument is connected via a wired or wirelessconnection to an external interface. In one configuration, theinstrument interacts with intestinal or colonic tissue and measurestissue oxygenation at or near the site of a surgical anastomosis. Theinstrument may take measurements before, during, and after theanastomosis is created. It may be used as a stand-alone device or incombination with an additional sensing instrument such as a sensinganvil for a surgical stapler. This configuration or another embodimentof an interrogator may be used to take measurements on the internaland/or external surface of tissue. It may take measurements at a singlelocation or at a plethora of locations.

FIG. 4a shows a representative embodiment of an anvil 401 for a surgicalstapler instrument with sensing capabilities. Working surface 403 makescontact with the biological tissue. Sensing elements 405 make contactwith tissue at working surface 403. The sensing elements may be anintegral part of anvil 401 or an accessory. In one configuration, thesensing elements are integrated into an accessory 409 that couples tothe anvil. The present invention includes sensing elements both directlyintegrated into and also otherwise associated with the surgicalinstrument (i.e. an accessory or adjunct device). FIG. 4b shows onerepresentative configuration of the present invention with sensingelements incorporated into cutouts 422 in the face of working surface ofa modified surgical stapler anvil 420. In one embodiment, anvil 420contains a sensor element interface circuit 426 couples via a flexiblecable to a control circuit 430. Control circuit 430 may contain aprocessor for controlling and interpreting sensor elements. The controlcircuit may communicate via a wireless transceiver 432. The device ispowered via a battery 436. All components are contained within a shell,cap or cover 438. FIG. 4c further details one embodiment where optical446 and mechanical sensing elements are integrated into the cavities inface 441 of the anvil between staple forms 442. 444 represents amechanical sensor such as a pressure transducer die that measurescompression pressure on surface 442 of the anvil. 445 represents anintegrated temperature sensor. 446 and 447 represent optical sensorelements, where 446 are one or more light emitters and 447 is aphotodetector. In one embodiment the optical sensor elements includemultiple light emitters at more than one peak wavelength so as to enabledepth-resolved sensing. Sensor elements 444-447 may be located in thecavities in various configurations including combined together ordistributed across the surface 441. A cover lip 448 encloses the edge ofthe sensor elements. In one embodiment, the sensing components areincorporated into a shell that couples to a surgical stapler anvil, oralternatively to the stapler body or other component. In anotherembodiment, the sensing components are incorporated directly into ananvil for a surgical stapler and replace a traditional non-sensinganvil. In both cases, the sensing shell or replacement anvil serve as anaccessory or adjunct to the surgical stapler and may be optionallycoupled to the stapler. The sensing anvil may be used as a stand-alonedevice or in combination with an additional instrument such as aninterrogator.

FIG. 4d shows a representative embodiment of a surgical stapler anvil450 with sensing capabilities according to the present invention. Anvil450 contacts tissue 452 and compresses tissue 452 against a surgicalstapler housing 454. Anvil 450 is coupled to housing 454 via a stalk456. Surgical staple forms are integrated into working surface 460 ofthe surgical stapler anvil 460. In one embodiment of the invention, oneor more sensors or sensor elements 464 are incorporated into cavitiesformed in the working surface 460 between staple forms. In oneembodiment, sensors or sensor elements 464 are configured to measureoxygenation of tissue 452 by interrogating a probe in medium 468 whichhas been injected into said tissue. In one embodiment, medium 468contains a phosphorescent probe whose lifetime is indicative of oxygencontent and sensor elements 464 comprise light emitters and detectors.Sensors or sensor elements 464 may also comprise pressure sensors fordetecting contact or compression pressure on tissue 452. Sensors orsensor elements 464 may also comprise temperature sensors and/or pHsensors. Sensors or sensor elements 464 are coupled to a processor orsignal processor 470. In one embodiment, processor 470 controls one ormore light emitters, receives signal from one or more light detectors,and determines oxygenation responsive to said signals. Processor 470 mayalso utilize pressure sensor data for gating a reading to a predefinedpressure to ensure consistent readings. Processor 470 may also utilizetemperature and/or pH sensor data for calibrating the oxygenationmeasurement. In one embodiment, an applicator 474 is coupled with anvil450. Applicator 450 may contain a medium 476 or be coupled to a syringeor other vessel containing the medium. Applicator 474 may contain one ormore needles or a microneedle array 478 to inject the medium into thetissue 452 as represented by 468. Applicator 474 may be a standalonedevice or integral to anvil 450. Applicator 474 may be keyed to anvil450 so as to delivery a microinjection at the location of sensorelements 464.

In one embodiment of the present invention, the surgical instrumentcontains LEDs, lasers, or other light sources on the working surface ofthe surgical instrument that introduce excitation light into aphosphorescent or fluorescent medium delivered into a tissue in contactwith said surface. Re-emitted light (i.e. fluorescent or phosphorescentemission) is sensed by PDs, avalanche photodiodes (APDs),photo-multiplier tubes (PMTs), SiPMs, or other photodetectors. Controlelectronics measure the time response of the oxygen-dependent quenchingof the phosphorescent response and said information is used to determinetissue oxygenation. Time domain or frequency domain based techniques maybe used to determine tissue oxygenation. In one embodiment, the mediumincorporating phosphorescent oxygen sensing probes may be introducedusing an injector integral to the surgical instrument. Microneedle,needle arrays, surface absorption, or other approaches may be used tointroduce the medium. An injection system may be incorporated into thesurgical instrument. In another configuration, a separate injectionsystem is utilized which may be by traditional means (i.e. needle andsyringe) or a stand-alone injector specifically designed to operate withthe instrument. In one configuration, a stand-alone injector is keyed tothe sensing anvil to align injection locations with sensor locations.These techniques may be applied to a laparoscopic interrogator, astapler, a laparoscopic or other minimally invasive instrument, arobotic instrument, or an instrument for open surgery.

FIG. 5 shows an oxygen imaging system for minimally invasive surgery.Instrument 501 enters body 503 through a standard port of laparoscopicor endoscopic surgery or an existing lumen of the body. The instrumentinterrogates tissue 505. Tissue 505 has a region 509 where a mediumcontaining a fluorescent or phosphorescent oxygen sensing probe has beenintroduced. In one embodiment, an injector 511 is incorporated into orcoupled into the instrument 501. In an alternative embodiment, othermethods of local injection or systemic bolus injection may be used.Instrument 501 incorporates an imaging system 513 at the distal end. Theimaging system 513 illuminates the probe in region 509 and detects theoxygen-dependent quenching of the phosphorescent response. In oneembodiment, imaging system 513 incorporates a camera and the systemprovides a 2D map of tissue oxygenation. The imaging system 513 may takeon multiple embodiments which may comprise a standard camera (such asCCD or CMOS), an intensified camera system, linear array, or scanningsensor. Imaging system tip 513 may directly contain the camera, or itmay be fiber optically coupled to a remote camera system. The map mayappear as a quantitative image of tissue oxygenation, and may be furthervisualized in combination with traditional endoscopic video images. In afurther embodiment, a 3D map conforming to the tissue shape isgenerated. The 3D map may be generated by registering multiple imagesfrom a single camera (such as using shape from motion techniques) orfrom multiple cameras (such as a stereo camera). One embodiment of theinvention is a miniature sensing instrument 501 for assessingoxygenation inside of the eye. The instrument may measure oxygenation ata single location or by generating a 2D or 3D quantitative map ofoxygenation. To minimize the tip of the miniature sensing instrument,optical fibers or other light guides couple the imaging system tip 513to a remote detector. The system can detect and map areas of high and/orlow oxygen or blood flow.

FIG. 6 shows a configuration where a circular surgical stapler deliversa sensing device 605 on its working surface 607. The sensing deviceplaces a plethora of optical fibers around an anastomosis 609. Fiberbundle 611 passes through the anus 615 to interrogator 617. In oneembodiment, the interrogator is configured to assess the phosphorescentlifetime of oxygen-dependent quenching of an injectable oxygen sensingprobe. In a further embodiment, the sensing device 605 is bioabsorbableand the optical fibers can be readily removed at a time after thesurgical procedure.

FIG. 7 shows a configuration of the invention where sensing elements areincorporated into a flexible substrate 701. One or more sensing elements705 are in contact with tissue 703. A medium containing phosphorescentoxygen sensing probes is introduced into tissue 703 and sensing elements705 illuminate the tissue and monitor the oxygen-dependent quenching ofthe phosphorescent response. The device may take the form of a patch. Itmay be applied internally or externally. The patch may be at leastpartially bioabsorbable. The invention may include an integratedinjection system or transdermal delivery system for the sensing medium.One configuration of the patch is for skin flap monitoring or organtransplant assessment. A further configuration is an externally wearablepatch to reliably provide tissue oxygenation in a clinical environmentthat is accurate across a wide range of oxygenations and robust tomotion artifact and other sources of error present in pulse oximetry orother traditionally used techniques.

In one embodiment of the invention, the phosphorescent oxygen sensingmolecular probes are coupled to a ferromagnetic material and substrate701 contains an apparatus for manipulating the probe location, orclearance rate. In one configuration, magnets including permanent,switched permanent, or electromagnets are integrated into or otherwisecoupled to substrate 701. The magnets attract the probes in the mediumto ensure that they remain in the tissue 703 within range of the sensingelements 705. In a further embodiment, the probe is configured with asize appropriate to maintain its location in the tissue for a period oftime. The size of the probe is configured such that it remains in tissue703 without migrating such that sensing may be performed without theneed for multiple or continuous injection. The probe may be sized suchthat it does not migrate, that it clears naturally after a delay, orthat it clears rapidly. In a further embodiment, bioabsorbablecomponents are coupled with the probe, such that the probe will haveminimal migration while the bioabsorbable components are in place. Aftera period of time the bioabsorbable material no longer impedes migrationor clearing of the probe and it can clear from the tissue 703 and thebody. The above described techniques are not limited to use with theembodiment of the patch shown in FIG. 7 and may be applied to otherembodiments.

FIG. 8 shows a microinjection system integrated into surgical instrument801. Needles 803 protrude from surface 805 into a tissue. In oneembodiment, needles 803 are controlled so as to only protrude pastsurface 805 upon reaching a specific tissue compression pressure. Needle803 may be a microneedle array. The array may be micromolded. In anotherconfiguration, needles 803 are porous needles that deliver the mediumalong their length into the tissue. In one embodiment, an injectionsystem and vessel 809 are contained in the body of instrument 801 andconnected through a tube 811 to needles 803. In an alternate embodiment,a bladder or cavity is collocated with the needle or needle array andused to deliver the medium. In one configuration of the needles 803 arearranged in along a line (straight or curved), and sensing elements areplaced along one or both sides of the needles.

FIG. 9a details one embodiment of an injection/applicator subsystemconfigured to deliver medium from apparatus into target biologicaltissue. A sealed vessel 901 containing medium with light re-emittingmolecular probe 903 is incorporated into the body of a surgicalinstrument 905. The vessel is comprises an outer shell 909, and aplunger 911. The plunger 911 is configured to mate with needle carrier915. The surgical instrument has a vessel receiver comprising a body919, and a needle subunit 921. The body 919 of vessel receiver 921receives the outer shell 909 of the vessel 901. The needle subunit 921comprises a body 925, a hollow needle 927, and a breakable stop 929. Theneedle body 925 receives the plunger 911. The initial position 931 ofthe plunger 911 within needle unit body 925 abuts up against breakablestop 929. The needle 927 is configured such that during initialpositioning of the plunger against the breakable stop, the needle isembedded in the plunger, not in contact with the medium. The other endof needle 927 is coupled to a tubing or manifold 949 which conveysmedium 903 to needle(s) 956. The user can inject discrete amounts ofmedium 905 into the tissue 954 through needle(s) 956 at the instrumentstissue contacting surface 958 by manipulating knob 935. Knob 935comprises a ratcheting mechanism 937 allowing for rotation in onedirection, at discrete increments. The knob is fixed to actuator rod939. Rod 939 extends from knob into surgical instrument body 905. Thedistal end of the rod holds a pin 941. The pin 941 mates with constantor variable pitch threads 943 in pusher unit 945. The pusher unit 945abuts against vessel shell 901. To inject the medium 903 into the tissue954, the knob 935 is rotated, which turns rod 939. The subsequentrotation of pin 941 advances the pusher unit 945, and vessel 901 intothe vessel receiver 921. Initial rotation of the knob 935 advances theplunger past the breakable stop 929, to final position 933, resulting incommunication of needle 927 with medium 903 and priming of needle(s) 956with medium. Further rotation of knob 935 results in discreteadvancement of vessel 901 and ejection of the medium 903 from the vessel901 in one or more controlled doses shows in tissue 954 as 950. Anoptional indicator 947 can be incorporated into surgical instrument 905to indicate state of actuation and dose number. Actuation of theinjection system may be either manual or electronically actuated. Themedium 903 may be contained in a prefilled vial 901 in the form of asolution or it may be packaged in dried lyophilized form andreconstituted at the time of use. FIG. 9b shows three states of theinjector: the initial sealed state, the punctured state, and theexpended state.

FIG. 10 shows an instrument 1001 inside body 1003, interrogating tissue1007. Sensing elements are integrated into jaw 1009. A medium isinjected into tissue 1007. The medium is ferromagnetic. In oneconfiguration, magnetic components are placed in the tip of instrument1001 along jaw 1009 to control the flow of the medium. In oneconfiguration, a medium is injected systemically or locally, and magnets1013 attract the medium or component therein to the sensing elements orslow the flow away from the sensing elements. In another configurationthe magnetic components are controllable to manipulate the medium, orparticles therein. The magnetic field may be manipulated by movingpermanent magnets, switching electro-permanent magnets, adjusting powerto electromagnets, or controlling the relative position of the jaws tothe tissue and/or medium in the tissue. The magnetically controllableparticles or medium may be used in sensing applications, or may be fordelivering therapy.

In a configuration of the invention, the probe is coupled withferromagnetic material such that it is possible to control its deliveryvia magnetic forces. In another configuration, the probe is coupled withbioabsorbable entities that protrude from the surface. Said entitiesallow the locally injected probe to remain at or near the injection sitefor a period of time. After which time, the bioabsorbable entities willdissolve and the probe will be free to clear from the body.

FIG. 11 shows an exemplary representation of a minimally invasive wandinterrogator instrument. The instrument 1101 has a tissue contactingdistal end 1103. In one configuration, the distal end 1103 isarticulated with respect to the main body of instrument 1101 at joint1107. Joint 1107 may have one or more degrees or freedom ofarticulation. The articulation is controlled from an actuator 1109 onthe body of the instrument. Actuator 1109 may be a slider, a knob, amotorized or robotic motion, or an alternative means of controlling thearticulation of joint 1107. Joint 1107 may take the form of a rigidhinge or pivot joint or a series of hinged pivots. Alternatively, joint1107 may be compliant in one or more degrees of freedom. In oneconfiguration, joint 1107 is a flexure joint actuated using shape memoryalloy (SMA) or other flexible cables or rods that are controlled bymoving a handle 1109.

Distal end 1103 contains two tissue contacting components, upper jaws1113 and lower jaw 1115. The instrument is manipulated to place abiological tissue (e.g., colonic tissue) between jaws 1113 and 1115. Atissue compression device 1117 is used to compress the tissue againstsurface 1119 of jaw 1113. Compression device 1117 is capable of ensuringa consistent, standardized pressure along surface 1119. In oneembodiment, compression device 1117 is a balloon or bladder which isinflated through tube 1121 through pneumatic or hydraulic means. Thedevice 1117 may incorporate one or more pressure sensors to ensureappropriate pressure is achieved. Pressure may be controlledautomatically or manually with actuator or inlet 1123.

One or more sensing elements 1127 and 1129 are integrated into orcoupled with face 1119. The sensing elements may include any of thepreviously described sensor types for measuring physiologic ormechanical properties. In one configuration, the sensing elementsinclude LEDs 1127 and PDs 1129, but may also take the form of otherpreviously described emitters and detectors. In a further embodiment,the LEDs and PDs alternate across and along each of two rows. In oneembodiment, the optical sensors use oximetry techniques where one ormore wavelengths of light are emitted into the tissue and the absorptionproperties as detected by the PDs are used to assess tissue oxygenation.In one embodiment, the LEDs are configured to optically excite aphosphorescent probe injected into the tissue and the PDs detect thephosphorescent response in order to assess the oxygen-dependentquenching time. Control electronics 1133 are integrated into theinstrument, and may be located in upper jaw 1113 of tip 1103. Additionalelectronics 1135 may be placed in the main proximal body of instrument.In one configuration, control electronics 1133 in jaw 1113 control thesensing elements and an additional set of control electronics 1135 inthe main body include a power source, wired or wireless communication,and user interfaces. User interfaces may include one or more buttons,displays, or audio devices. In one configuration control electronics1133 manage control of the sensing elements 1127 and 1129 and determineinformation about the oxygen-dependent quenching time that is used toassess tissue oxygenation at one or more points along surface 1119.

In one embodiment, needles 1137 are used to locally inject a mediumcontaining the phosphorescent oxygen sensing probe. The needles 1137 maybe small standard needles, a micromolded needle array, porous needleswith individual or a plethora of holes on the side and occluded tips, orother variations for distributing the medium in the tissue. In oneconfiguration multiple needles 1137 and multiple sensing elements 1127and 1129 provide a distribution of oxygenation in the tissue along face1119. Needles 1137 may be configured to inject varying amounts tovarying depths in the tissue. In one configuration, the sensinginstrument is configured to asses a distribution of tissue oxygenationalong both sides of layered or tubular tissue. LEDs 1127 sequentiallyemit two wavelengths, and the time response for each wavelength providesinformation about the oxygen-dependent quenching at different depths inthe tissue as described previously. In one configuration, one or moreneedles 1137 are inserted laterally along the length of the jaws throughthe tissue.

The needles 1137 are connected through tube 1141 to reservoir 1143. Tube1141 may pass through the center axis of articulated joint 1107.Reservoir 1143 contains medium 1145. The medium may contain aphosphorescent oxygen sensing molecular probe. In one embodiment,plunger 1149 is used to inject metered doses of medium 1145 from sealedvessel 1143. The vessel 1143 may contain a specific number or predefineddoes of the medium 1143. In one embodiment, an actuation device 1153controls the motion of piston 1149. The actuation device 1153 may be ascrew or ratcheting device controlled by the user. It may take the formof a motorized or robotic actuation. The sensing instrument may be usedwith either locally injected medium, or systemically injected medium.Locally injected medium may be delivered using apparatus associated withthe sensing instrument as described, or may be injected using astand-alone device. In one configuration, a stand-alone device is placedbetween jaws 1113 and 1115 and the medium is ejected into the tissue.Jaws 1113 and 1115 may be fixed, move in a parallel motion, or close ina hinged motion.

The sensing instrument 1101 may be used as a stand-alone device. In analternate configuration, a wired or wireless connection 1157 connects toa base station and/or one or more sensing instruments. The instrumentmay be a minimally invasive surgical instrument, used for traditionalopen surgical procedures, or configured for external use. The techniquesshown in FIG. 11 are directly applicable to other surgical instruments.In one embodiment, instrument 1101 is a surgical stapler anvil. Theanvil has a face 1119 that incorporates staple forms Sensing elements1127 and 1129 are configured such that they are at the tissue contactface of surface 1119. Needles 1137 may be integrated into the anvilsurface 1119, an opposing surface, or an internal cavity. In oneconfiguration, reservoir 1143 is contained inside a cavity in the anviland a plunger 1149 is actuated as the anvil compresses the tissueagainst an opposing surface, thus injecting the tissue with the medium1143 as the stapler is closed and the anvil is compressing the tissueagainst an opposing surface on the stapler body. In one configuration,the medium 1143 is contained in a reservoir in a separate apparatuswhich is placed between the anvil and the opposing surface. In thisconfiguration, the reservoir is compressed and ejects the medium intothe tissue as the anvil compresses the tissue. This invention includesconfigurations of the described embodiments wherein an injection systemis contained within the sensing device and also configurations whereinthe injector is external to the sensing device and may be operatedindependently.

FIG. 12 shows one embodiment of the invention, where sensors are coupledwith a bite block or other piece of medical equipment 1201 attaching toa patient's face 1203. In one configuration, a bite block 1201 is placedover the mouth of patient 1203. Bite block 1201 has a guide 1205 andclamping device 1207. In one configuration, bite block 1201 isconfigured to hold an endotracheal (ET) tube 1217. In one configuration,ET Tube 1217 incorporates or is coupled to a sensor 1219 at the distalend. Sensor 1219 may be a single point sensor, a multi-point sensor, oran imaging array. In another configuration, sensor or sensors 1221 areplaced along the surface of the ET tube 1217. One or more sensors may beplace circumferentially and longitudinally along the tube. It should benoted that tube 1217 is shown as an ET tube as an example, however thepresent invention includes all such tubes, catheters, cannulas, scopes,needles, and similar rigid and flexible devices for insertion into themouth or other orifice of the body. Such sensing devices may be usedwith or without the block 1201. In one embodiment, sensor 1225 operatesinside of the patient's mouth. Sensor 1225 may be in contact with tongue1227. The sensor 1225 may rest on the surface of the tongue 1227, clipto the tongue, or sense sublingually. The sensor 1225 may also be usedto sense at other locations in or around the mouth including tongue,cheek, lips, or gums. In a further embodiment, a sensor 1231 is coupledto the block 1201 and in direct contact with the patient 1203. Thesensor 1231 may be in contact with the patient's face, cheek, lip, gum,or another external tissue.

It should be noted that these sensing techniques can be applied to othermedical devices 1201 attached to patient 1203. In one exemplaryconfiguration, a mask 1201 is placed over the patient. One or moresensors 1231 may be coupled with the mask itself, or one or more sensors1215 may be coupled with the strap 1213. Similarly, sensors 1215 mayreside in a band or strap that may or may not contain another medicaldevice, and may be affixed to the head or other part of the body. In oneconfiguration, a sensor may be used to determine tissue oxygenation orother properties at the skin surface, or at a depth below the surface.Such sensing may include assessing tissue oxygenation or otherproperties of tissue within the skull. A further exemplary configurationis a wearable strap or band 1213 with one or more sensors 1215 coupledwith it. In one embodiment, one or more of sensors 1215, 1219, 1221, and1231 are configured to sense oxygenation through the use ofphosphorescent oxygen sensing probes as described herein. In a furtherconfiguration, injection devices to introduce a medium containing theprobe may be coupled with the sensors. In an alternate configuration,the probe is injected locally by other means or systemically. Thedescribed techniques for manipulating the position or flow of the probemay be applied with this device, as with other devices presented in theinvention. The sensors 1215, 1219, 1221, and 1231 may be configured tosense oxygenation by oxygen-dependent quenching of a phosphorescentprobe, tissue spectroscopy, pulse oximetry, or other means, and/or maybe configured to sense blood flow or perfusion, and/or may be configuredto sense mechanical properties of the tissue or tissuesensor-interaction. In one embodiment the device takes the form of abite block or indwelling line/tube such as an intracranial,endotracheal, oro/naso gastric tube, venous catheter, arterial catheter,chest tube, feeding tube, urinary catheter, or rectal tube. The sensorelements are positioned on said tube in a manner such that they contactbiological tissue. Phosphorescent medium is either systemically orlocally injected into subject tissue. Previously described techniquesfor injection as well as maintaining the location of the medium in thevicinity of the sensor may be utilized with the configurations describedherein.

FIG. 13a shows an embodiment of the present invention configured forophthalmologic applications, such as retinal surgery. The figure showseye 1301 of patient 1303 with cornea 1309, lens 1311, and iris 1313. Inone embodiment, a surgical instrument or imaging device 1331 is used toassess oxygenation or perfusion in retina 1315 or at optic nerve 1319.In one configuration, instrument enters the vitreous 1323 of the eyethrough the sclera 1327. The present invention describes a sensinginstrument that can be inserted into the eye through the sclera 1327, orthrough another entry point and is capable of sensing oxygenation,perfusion, or other physiologic or mechanical properties within the eye1301. In one configuration, instrument 1331 includes a sensor or sensingelement 1335 at the distal end of the instrument. The sensor 1335 maycome in direct contact with the retina 1315 (or other feature), or maybe used at a distance from the surface. Sensor 1335 may be a singlepoint sensor, an imaging system such as a camera system, or a fiberopticor other light transmission bundle connecting to an external imagingsystem. The previously described mapping and imaging techniques may beused. In one configuration a micro camera system is utilized at the tip1335 of the instrument. In another configuration, light guides such asan optical fiber bundle or other means of light transmission such asGRIN lenses are utilized to couple tip 1335 with a remote detectordistal to instrument 1331 such as a camera. Sensor 1335 may be used toassess tissue oxygenation at a single location, swept to generate a mapof tissue oxygenation, or may directly generate a 2D map.

In one configuration, an injector or injection system 1339 is used toinject a medium containing an oxygen sensing molecular probe into theretina 1315 or other tissue. In other configurations, an externalinjector provides a local injection of the probe or a systemic injectionis performed to infuse the tissue with the oxygen sensing probe. Theinstrument 1331 may be manipulated manually, or it may be moved using arobots or other externally controlled means. In one embodiment,instrument 1331 is manipulated to scan sensor 1335 across the tissuesurface to determine the oxygenation and/or other properties at multiplepoints. In a further configuration, by manipulating the tool, a 2D or 3Doxygenation map of the retina 1315 is generated. The map may be fusedwith camera-based imaging to generate an overlay of oxygenation or flowon a video steam or captured still image. In one configuration,traditional endoscopy images are collected along with quantitativeoxygen maps and are visualized together. In another embodiment, theimaging device does not enter the vitreous 1323, and rather images theoxygenation in the eye through lens 1311. The sensing instrument may bea stand-alone device, used in conjunction with imaging or surgicalequipment such as an endoscope, or integrated into or coupled with suchimaging or surgical equipment. In a further embodiment, sensor 1335 ofinstrument 1331 is configured to image beyond the retina to a pointwithin the skull, including the brain. The described sensor 1335 may beconfigured to assess tissue oxygenation based on oxygen-dependentquenching of a molecular probe as described herein. It may furtherincorporate other optical or mechanical sensing techniques as describedelsewhere in this disclosure.

FIG. 13b shows an embodiment of the invention where the sensing device1351, or component thereof, is external to the eye 1301. The sensingdevice 1351 rests on or is external to the cornea 1309 for non-invasivesensing of oxygenation in the eye. In one configuration, sensing device1351 takes the form of a contact lens or other similar objectsubstantially made of hydrogel or similar material and rests on cornea1309. In another configuration, sensing device 1351 is a patch thatrests over the eye 1301 and may rest on face 1303. In an alternateconfiguration, the sensing device 1351 is externally mounted. Oneexample of an externally mounted device 1351 is coupled to orincorporated into a surgical microscope. In another embodiment, thesensing device 1351 is mounted to or incorporated into a pair of eyeglasses, goggles, or eyewear. In another embodiment, sensor 1351 isconfigured to act as a biometric device interrogating retina 1315, orthe optic nerve 1319 to aid in identification of an individual.

Sensing device contains one or more sensing elements 1355. The sensingelements may be integral parts of sensing device 1351, or connected viaoptical fibers, wires, wireless, or other means. In one embodiment, thesensing device is configured to assess oxygenation through optical meansof monitoring an injected molecular phosphorescent probe that hasoxygen-dependent phosphorescent quenching characteristics. In oneconfiguration the sensing elements 1355 emit one or more wavelengths oflight 1357 through the eye's lens 1311 such that it focusses on a point1359, such as the fovea, on the optic nerve 1319. One application of theinvention is to assess oxygenation of the optic nerve, as a proxy forbrain oxygenation. In another application, the invention is used todetermine a map of oxygenation at and near the optic nerve 1319 and/oron the retina 1315. The exemplary embodiment of an oxygen imaging system(i.e. oxygen mapping system) shown in FIG. 3 is only an exampleconfiguration and this approach may be utilized in other configurationsfor other organ systems. In a further embodiment, this approach isutilized for assessing oxygenation of gastrointestinal tissue. It may befurther utilized in the previously described approach to measureoxygenation before, during, and after CRC surgery.

Accordingly, one embodiment includes a surgical device for sensingtissue oxygenation based upon oxygen-dependent quenching ofphosphorescent oxygen sensing probe.

Another embodiment includes a minimally invasive surgical deviceconfigured to sense oxygenation of a tissue, wherein the sensing isbased upon oxygen-dependent quenching of a phosphorescent oxygen sensingprobe, wherein the surgical device contains a mechanism for ensuringconsistent compression pressure the tissue.

Another embodiment includes a surgical instrument for manipulatingbiological tissue, wherein the instrument incorporates an injectionsystem configured to deliver a medium consisting in part of oxygensensing probes to the tissue, wherein the instrument furtherincorporates a sensing system configured to detect the optical responsethe oxygen sensing probes in the tissue.

Another embodiment includes a surgical instrument for manipulatingbiological tissue, wherein the instrument incorporates a microneedlearray configured to inject a medium into the tissue.

Another embodiment includes a surgical instrument for manipulationbiological tissue, wherein the instrument incorporates a microinjectionsystem into the body of the instrument, wherein the instrument furthercomprises one or more needles, wherein the microinjection systemcontrols injection of a medium into the tissue through the one or moreneedles.

Another embodiment includes a surgical instrument for manipulatingbiological tissue, wherein the instrument comprises a means forproducing constant compression pressure of the tissue against a surfaceof the instrument.

Another embodiment includes a method for manipulating an injectableprobe, wherein the probe incorporates ferromagnetic material, andwherein a surgical instrument incorporates magnets to attract and retainthe molecule.

Another embodiment includes a surgical instrument incorporating a meansfor injection of medium into tissue, and further incorporates a meansfor manipulating the location of the medium in the tissue afterinjection.

Another embodiment includes a method for maintaining the position of alocally injected probe at the injection site in a tissue for a period oftime, wherein bioabsorbable entities are incorporated into the probesstructure, wherein the bioabsorbable entities detach from the probe andenable clearance from the body.

Another embodiment includes a surgical instrument comprising a highspeed imaging system, wherein the imaging system is configured toprovide data to generate maps of tissue oxygenation based uponphosphorescent optical response of an injectable oxygen sensing probe.

Another embodiment includes a surgical instrument for eye surgerycomprising an imaging system, wherein the imaging system is configuredto provide data to generate maps of tissue oxygenation based uponphosphorescent quenching time of an oxygen sensing probe.

Another embodiment includes a method of sensing and discriminatingoxygenation in two or more layers of tissue, wherein oxygenation issensed based on phosphorescent quenching time of a phosphorescent oxygensensing probe, wherein the probe has multiple absorption wavelengthsthat have different tissue absorption properties, wherein the oxygen isdiscriminated based on the phosphorescent response due to multipleemission wavelengths.

Another embodiment includes a surgical system comprising a surgicalinstrument configured to assess tissue oxygenation, and furthercomprising a sensing device configured to assess tissue oxygenation thatcouples to a surgical stapler, wherein both devices are configured toassess oxygenation of tissue using an injectable phosphorescent oxygensensing probe, wherein the system is configured to provide informationto guide a surgical procedure.

Another embodiment includes a surgical instrument comprising a pluralityof sensing elements, wherein at least the instrument is configured toassess tissue oxygenation based on the quenching time of an injectablephosphorescent probe, wherein the instrument is further configured tosense at least one of tissue oxygenation, blood oxygenation, pulse rate,pulse presence, pulse rhythm, tissue perfusion, staple gap, compressionforce, tissue interaction force, fluorescence, tissue electricalimpedance, tissue electrical activity, pH, concentration of cellularrespiration metabolites, electromyography, temperature, fluid flow rate,fluid flow volume, tissue pressure, blood pressure, biomarkers,radiotracers, immunologic characteristics, biochemical characteristics,nerve activity, an evoked potential, oxygen delivery, oxygenutilization, tissue characterization, tissue general health, tissue flowdynamics, tissue chemical composition, tissue immunologic activity,tissue pathogen concentration, tissue water content, blood hemoglobincontent, tissue chromophore content, tissue neoplastic cell content andtissue dysplastic cell content.

Another embodiment includes a surgical instrument configured to assesstissue oxygenation based on the quenching time of an injectablephosphorescent probe, wherein the instrument is communicatively coupledvia a wireless connection to a base station.

Another embodiment includes a sensing surgical stapler anvil, whereinthe sensing anvil is configured to assess oxygenation of tissue at thesite of an anastomosis, wherein the assessment of oxygenation is basedon the quenching time of an injectable phosphorescent probe.

Another embodiment includes an adjunct to a surgical staplerincorporating at least one sensor configured to assess the oxygenationof a tissue based on the quenching time of an injectable phosphorescentprobe, wherein the adjunct operates independently of the stapler;wherein adjunct is optionally coupled to the stapler.

Another embodiment includes a medical device configured for sensingtissue oxygenation, the device comprising at least one sensor, whereinat least one sensor of the device detects the optical response of anoxygen sensing probe.

The oxygen sensing probe has a phosphorescent optical response, whereinthe phosphorescent lifetime of the optical response is responsive tooxygen-dependent quenching.

The medical device may be a surgical instrument for manipulatingbiological tissue.

The medical device may be a minimally invasive surgical instrument.

The surgical instrument further comprises a mechanism for ensuringconsistent compression pressure on the tissue.

The surgical instrument may further comprises an injection systemconfigured to deliver a medium to the tissue, wherein the mediumincludes the oxygen sensing probes.

The injection system may comprise a plethora of microneedles.

The surgical instrument may be a surgical stapler or component thereof.

The surgical instrument may be a surgical stapler anvil with integratedoxygen sensing capabilities.

The medical device may be patch with integrated oxygen sensingcapabilities.

The patch may be fully or partially bioabsorbable.

The medical device may be communicatively coupled via a wirelessconnection to a base station.

A surgical stapler anvil may be configured to assess oxygenation of abiological tissue at the site of an anastomosis, wherein the assessmentof oxygenation is based on oxygen-dependent quenching time of aninjectable phosphorescent probe.

An adjunct to a surgical stapler incorporating at least one sensor maybe configured to assess oxygenation of a biological tissue, wherein theassessment of oxygenation is based on oxygen-dependent quenching time ofan injectable phosphorescent probe, wherein the adjunct operatesindependently of the stapler; wherein adjunct is optionally coupled tothe stapler.

A surgical system may include a surgical instrument configured to assessoxygenation of a biological tissue, and a sensing device configured toassess tissue oxygenation that couples to a surgical stapler. Thedevices are configured to assess oxygenation of biological tissue usingan injectable phosphorescent oxygen sensing probe.

The surgical system may be further configured to provide information toguide a surgical procedure.

An imaging system may be configured to provide a 2D map of tissueoxygenation, wherein the imaging system generates the map responsive tooxygen-dependent quenching of the phosphorescent response of oxygensensitive molecules.

The imaging system may be incorporated into a surgical instrument.

The surgical instrument may be configured for ophthalmic surgery,wherein the instrument provides an oxygenation map of the retina.

The surgical instrument may be configured to provide an oxygen map ofgastrointestinal tissue.

The surgical instrument may be configured to assist in analysis of atarget tissue, wherein analysis is performed for at least one of before,during, and after creation of an anastomosis.

A surgical instrument may manipulate ipulating biological tissue,wherein the instrument incorporates a microinjection system into thebody of the instrument, wherein the instrument further comprises one ormore needles, wherein the microinjection system controls injection of amedium into the tissue through the one or more needles.

A surgical instrument may manipulate biological tissue, wherein theinstrument comprises a means for producing constant compression pressureof the tissue against a surface of the instrument.

A method may manipulate an injectable probe, wherein the probeincorporates ferromagnetic material, and wherein a surgical instrumentincorporates magnets to attract and retain the molecule.

A surgical instrument may incorporate a means for injection of mediuminto tissue, and further incorporates a means for manipulating thelocation of the medium in the tissue after injection.

A method may maintain the position of a locally injected probe at theinjection site in a tissue for a period of time, wherein bioabsorbableentities are incorporated into the probes structure, wherein thebioabsorbable entities detach from the probe and enable clearance fromthe body.

A method of sensing and discriminating oxygenation in two or more layersof tissue may be provided, wherein oxygenation is sensed based onphosphorescent quenching time of a phosphorescent oxygen sensing probe,wherein the probe has multiple absorption wavelengths that havedifferent tissue absorption properties, wherein the oxygen isdiscriminated based on the phosphorescent response due to multipleemission wavelengths.

A surgical instrument may comprise a plurality of sensing elements,wherein at least the instrument is configured to assess tissueoxygenation based on the quenching time of an injectable phosphorescentprobe, wherein the instrument is further configured to sense at leastone of tissue oxygenation, blood oxygenation, pulse rate, pulsepresence, pulse rhythm, tissue perfusion, staple gap, compression force,tissue interaction force, fluorescence, tissue electrical impedance,tissue electrical activity, pH, concentration of cellular respirationmetabolites, electromyography, temperature, fluid flow rate, fluid flowvolume, tissue pressure, blood pressure, biomarkers, radiotracers,immunologic characteristics, biochemical characteristics, nerveactivity, an evoked potential, oxygen delivery, oxygen utilization,tissue characterization, tissue general health, tissue flow dynamics,tissue chemical composition, tissue immunologic activity, tissuepathogen concentration, tissue water content, blood hemoglobin content,tissue chromophore content, tissue neoplastic cell content and tissuedysplastic cell content.

The embodiments described above demonstrate how oxygen sensitive probescan be utilized with surgical instruments incorporating sensors. Theseembodiments are meant as illustrative purposes. The described sensinginstruments and approaches can be adapted to provide the describedfunctionalities for other surgical instruments or medical devices.Further, the techniques discussed should not be construed to be limitedto use only with phosphorescent oxygen sensing probes. Further still,all references to phosphorescence or fluorescence more broadly may beapplied to all light-remitting phenomenon.

The present invention can be practiced by employing conventionalmaterials, methodology and equipment. Accordingly, the details of suchmaterials, equipment and methodology are not set forth herein in detail.In the previous descriptions, numerous specific details are set forth,such as specific materials, structures, chemicals, processes, etc., inorder to provide a thorough understanding of the present invention.However, it should be recognized that the present invention can bepracticed without resorting to the details specifically set forth. Inother instances, well known processing structures have not beendescribed in detail, in order not to unnecessarily obscure the presentinvention.

Only exemplary embodiments of the present invention and but a fewexamples of its versatility are shown and described in the presentdisclosure. It is to be understood that the present invention is capableof use in various other combinations and environments and is capable ofchanges or modifications within the scope of the inventive concept asexpressed herein.

Although the foregoing description is directed to the preferredembodiments of the invention, it is noted that other variations andmodifications will be apparent to those skilled in the art, and may bemade without departing from the spirit or scope of the invention.Moreover, features described in connection with one embodiment of theinvention may be used in conjunction with other embodiments, even if notexplicitly stated above.

1. A surgical instrument configured to sense a light re-emitting probeto resolve tissue oxygenation, the surgical instrument comprising: atleast one optical emitter that is configured to excite the lightre-emitting probe within an absorption band of the light re-emittingprobe; at least one optical detector configured to receive there-emitted light from the probe; and a signal processor that isconfigured to resolve the tissue oxygenation based on the receivedlight. 2.-30. (canceled)